The document discusses the formulation and evaluation of oral fast dissolving films of Donepezil Hydrochloride for the treatment of Alzheimer's disease. Various polymers like HPMC, Pullulan, and PVA are screened for their film forming properties. The optimized formulation will be developed using a factorial design to study the effect of polymer concentration and plasticizer on the drug release.

1. 5 sept,2012
Sir,
You Guided Me When I Was Lost….
You Supported Me When I Was Weak….
You Have Enlightened me all through…..
1 9/05/2012

3.  Introduction
 Literature survey
 Objectives
 Plan of work
 Materials And Methods
 Result and Discussions
 Conclusion
3  References 9/05/2012

4.  Definition:- Oral film
It is relatively a new dosage form in which thin film is
prepared using hydrophilic polymers rapidly dissolves on
tongue or buccal cavity.
 Rapid onset of action and improved bioavailability.
 Useful for geriatric patients.
4 9/05/2012

5. 5 9/05/2012

6. Fear Water
Choking Dysphagia,Travelling
Fragile /
Brittle
Grittiness
Stability
Microbial
Cont.
Pain /
infection/inflammation
Dosing accuracy
6 9/05/2012
Large Dose

7. Alzheimers Disease
Is an irreversible ,
progressive brain disease
that slowly destroys memory
& thinking skills and ability to
carry out simple task.
Cause problems with memory,
thinking,& Behavior
Symptoms:
serious memory loss, Confusion,
Behavioral Changes, Difficulty in
Speaking/Walking
Treatment:
Mild to Moderate: Donepezil,
Galantamine,rivastigmine
Severe: Donepezil ,
Memantamine
7 9/05/2012

8. Alzheimers
Disease
Occurs to Geriatric
Patients
Each and every
day Patients has
to take Dosage
So,
Patient compliance
is the Key
parameter while
designing the DDS
8 9/05/2012

9. Patient Compliance :
Problems with Conven D.T Liquids MDT FDF
DDS tional (Emulsion
Tab/Ca /Susp./Syrup)
p
Water Needed X X X
Swallow/Coughing X X X
Choking Fear X X X
Dosing Accuracy X X X X
Vomisis X X
Dysphagia X X X
Travelling X X X
Mechanical X X X
Strength
Grittiness X X X X
Stability X X X X
Microbial X X X X
Contamination
9 FDF>MDT> Conventional TAB/CAP and Liquids 9/05/2012
X = No problems….DDS

10. Alzheimer's Disease
26.5 millions patients
in 2006
Market $ 6 Billions in
2011 in 7 major
markets
Molecule available for mild
to severe Alzheimer
So, DONEPEZIl is the
undisputed market leader
10 9/05/2012

11. Tab/MDT-Available in
India
FDF- Not available
in India
Donepezil
Hydrochlorid
e
11 9/05/2012

12. Sr AUTHOR TOPIC STUDY
1. Aggarwal J. et A Comparative investigation Polymers: HPMC E15; Gelatin,
al1 on different polymers Sodium alginate and polyvinyl alcohol ,
employed in the formulation pullulan
of Higher concentration of polymer
oral fast dissolving films and plasticizer resulted in increased
disintegration time
2 Kunte S et al7 Fast dissolving strips: A oral strips formulated with different
novel approach for the concentrations of HPMC E6 and
delivery of verapamil maltodextrin found to disintegrate in
less than 30 seconds.
3 Dinge A. et al5 Formulation and Evaluation  HPMC and xanthan gum
of Fast Dissolving Films for successfully taste masked by the use
Delivery of Triclosan to the of poloxamer 407 and eugenol
Oral Cavity (HPBCD) to improve solubility of
TC
12 9/05/2012

13. Literature survey……….
Sr AUTHOR TOPIC STUDY
4 Raju S et al 19 Flash release oral films of  HPMC , CMC
metoclopramide hydrochloride This case study showed that
for pediatric use: formulation hydroxypropyl methyl cellulose was the
and in-vitro evaluation most suitable film-forming material for
metoclopramide -loaded films,
providing fast dissolution films that
were not sticky and were easy to handle.
5 Saini S et al20 Fast dissolving film of 22 factorial design
levocetrizine dihydrochloride prepared by solvent casting method
by using Maltodextrin & HPMC E15
6 Cilurzo F. et Nicotine Fast Dissolving Films  The 'mint' and 'licorice' flavors
al4 Made of Maltodextrins and sucralose mixture resulted
appropriate to mask DS bitterness
TMAs did not significantly affect
the film disintegration time and
13 dissolution rate 9/05/2012

14. Literature survey……….
Sr AUTHOR TOPIC STUDY
7 Choudhry et al3 Formulation and solvent casting technique
evaluation of quick carboxy methyl cellulose, hydroxy
dissolving Film of propyl methyl cellulose and hydroxy
levocetirizine propyl cellulose
dihydrochloride . Neotame masked the bitter taste
of levocetirizine dihydrochloride
8 Prabhu P. et al26 Formulation and marked increase in the dissolution rate
evaluation of fast was exhibited by FDF of levocetirizine
dissolving films of dihydrochloride containing HPMC as
levocitirizine di a polymer, when compared to
hydrochloride conventional tablets.
9 Amin A et L 25 Formulation and Pullulan
characterization of Solvent casting
rapidly dissolving films bitter taste masking was achieved by
of cetirizine use of sweeteners- Aspartame,
hydrochloride using sucralose
pullulan as a film  dissolution media namely 0.1N HCl
forming agent and simulated saliva (500ml)
14 9/05/2012

15. Sr AUTHOR TOPIC STUDY
10 Mashru et al24 Development and salbutamol sulphate and polyvinyl
Evaluation of Fast alcohol
Dissolving Film of 33 factorial design
Salbutamol Sulphate Simulated saliva (300 mL) using USP
Apparatus 2 (paddles).
11 Reinhart Martin et Pivotal On the basis of bioequivalence assessed
al9 Bioequivalence study in this pivotal study, therapeutic
for Ondansetron equivalence between Ondansetron
Rapidfilm® RapidFilm™ and Zofran ODT® could
successfully successfully be demonstrated
completed
15 9/05/2012

16.  To formulate and evaluate oral fast dissolving films of Donepezil
HCl
 To study compatibility of Donepezil HCl with excipients
 To study the effect of different polymers on film forming capacity
and plasticizers on the release of Donepezil HCl
 To prepare the optimized oral fast dissolving film formulation of
Donepezil HCl by response surface methodology, Design Expert
software
16 9/05/2012

17. 17 9/05/2012

18. 18 9/05/2012

19. Usefulness
 Useful for geriatric patients
 Useful for uncooperative and admitted patients
 In travelling cases, Patients suffering from vomisis,
Dysphagia patients : FDF is better than conventional
tablets
19 9/05/2012

20.  Literature survey
 Selection and procurement of drug and excipients
 Preformulation study including characterization of drugs
 Identification of the drug
 Melting point
 UV spectrum
 FTIR spectrum
 DSC study
 Calibration curve of Donepezil Hydrochloride in 0.1 N HCl
and in Simulated saliva pH 6.8 by UV spectrophotometer

20 Drug - excipients compatibility study 9/05/2012

21.  Formulation development of fast dissolving film
 Formulation design for selection and optimization of film
forming polymer concentration
 Use of Factorial design for the formulation optimization of
fast dissolving film of Donepezil Hydrochloride
 Evaluation of fast dissolving film
 Analysis of Factorial design results by Design Expert software
21 9/05/2012

22.  Name: (RS)-2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-
2,3-dihydroinden-1-one
 Molecular weight: 415.95
 Melting Point : 231-2320C . HCL
 Bioavailability: 100 %
 Solubility: soluble in water
 MoA: centrally acting reversible acetyl cholinesterase inhibitor
 Use: in the treatment of Alzheimer’s disease where it is used
to increase cortical acetylcholine
 Dose : 5 -10mg, Maximum dose : 23 mg
22 9/05/2012

23. 23 9/05/2012

24. 24 9/05/2012

25. Concentration
Sr. No Absorbance * Calibration curve of Donepezil
(µg/ml) HCl in 0.1 N HCl
1 … …
2 … …
3 … …
4 … …
5 … …
6 … …
7 … …
8 … …
Parameter Range
Wave Length …….
Coefficient of 0.999
Correlation
Intercept 0.0336
Equation
25 Y= 0.0336x+0.024 9/05/2012
* Represents mean value

26. Concentration
Sr. No Absorbance* Calibration curve of Donepezil
(µg/ml) HCl in Simulated saliva pH 6.8
1 … …
2 … …
3 … …
4 … …
5 … …
6 … …
7 … …
8 … …
Parameter Range
Wave Length …. nm
Coefficient of 0.9989
Correlation
Intercept 0.031
Equation
26 Y= 0.031x+0.0178 9/05/2012
* Represents mean value

27. 27 9/05/2012

28. 28 9/05/2012

29. Sr.
Name of the Ingredient Category Name of Manufacturer Company
No.
1 Donepezil Hydrochloride Drug ……………
2 Pullulan Polymer …………….
…………….
3 HPMC E3,E5,E6,E15 Polymer
4 Polyvinyl Alcohol Polymer ……………
5 Glycerol Plasticizer …………….
6 Sucralose Sweetener …………….
29 9/05/2012

30. Sr. No. Instrument
1 UV Visible spectrophotometer
2 FTIR spectrophotometer
3 Magnetic Stirrer
4 Dissolution apparatus
5 Micrometer Screw Gauge
6 Stability Chamber
30 9/05/2012

31. Ingredient Percentag
Sr. no. e amount Examples
s
(%)
1 Drug 1-23 Antialzheimers etc
HPMC,Pullulan,
2 Polymer 40-50
Maltodextinn, Carbopol etc
3 Plasticizer 25-35 PG,PEG , Sorbitol
4 Sweetener 2-10 Sucralose, Aspartame
Peppermint ,
5 Flavor 2-5
31
Vanilla,Coffee,Chocalate9/05/2012

32. Evaluated on the
HPMC E3 basis of
11 Polymers
Polymers
Transparency
HPMC E5
Film Forming
HPMC E6 Screening of polymers Capacity
HPMC E15
PULLULAN Chitosan PVA
Pullulan HPMC
POLYOX
WSR 1105 ………….. (E3,E5,E6,E15) (.:….)
…….
PVA PVA
X (.:…………….)
SODIUM
X
ALGINATE
E
PVP
CHITOSAN HPMC E + PVA
GELATIN
……….. ……….. 9/05/2012
32

33. Plasticizer
Glycerol
PG
…….. …PEG……
……..
……….
Glycerol
Final Formulation: HPMC E + PVA + Glycerol
33 9/05/2012

34. Table 1: Effect of the Different polymers on film forming capacity of film
Polymer (2% E1 E2 E3 E4 E5 E6 E7 E8 E9 E10 E11
W/V)
HPMC E3 √
HPMC E5 √
HPMC E6 √
HPMC E15 √
PULLULAN √
POLYOX √
WSR 1105
PVA √
SODIUM √
ALGINATE
PVP √
CHITOSAN √
GELATIN √
D.W. √ √ √ √ √ √ √ √ √ (0.1N √
34 HCL)
9/05/2012
(…ml)

35. Table 2: Evaluation of Films prepared by using Explored polymers
*Film forming
Sr No. Polymers Used Appearance
capacity
1 HPMC E3 +++ Transparent
2 HPMC E5 +++ Transparent
3 HPMC E6 ++++ Transparent
4 HPMC E15 +++ Transparent
5 PULLULAN +++++ Very Transparent
6 POLYOX WSR 1105 - ----
7 PVA +++ Transparent
8 SODIUM ALGINATE - ---
9 PVP K30 + Semitransparent
10 CHITOSAN +++ Transparent
11 GELATIN - ----
35 9/05/2012

36. Table 3: Preparation of Trial batches with Pullulan Table 4: Preparation of Trial batches with Chitosan
Sr.No. Components P1 P2 P3 P4 Sr.No. Components C1 C2 C3 C4
1 Donepezil HCl (mg) … … … … 1 Donepezil HCl (mg)
2 Pullulan (mg) … … … … 2 Chitosan (mg)
3 Glycerol (ml) … … … … 3 Glycerol (ml)
4 PEG 400 (ml) … … … … 4 PEG 400 (ml)
5 PG (ml) … … … … 5 PG (ml)
6 D.W. (ml) … … … … 6 0.1N HCl (ml)
Table 6: Preparation of Trial Batches with HPMC E
Table 5: Preparation of Trial batches with PVA series polymer
Sr.No Components V1 V2 V3 V4
Sr.No. Components E1 E2 E3 E4
1 Donepezil HCl (mg) … … … … Donepezil HCl
1
(mg)
… … … …
2 PVA (mg) … … … …
2 HPMC E3(mg) … … … …
3 Glycerol (ml) … … … … 3 HPMC E5(mg) … … … …
4 PEG 400 (ml) … … … … 4 HPMC E6(mg) … … … …
5 PG (ml) … … … … 5 HPMC E15(mg) … … … …
6 D.W. (ml) … … … … 6 D.W.(ml) … … … …
36 9/05/2012

37. Table 7: Evaluation of Trial Batches of Pullulan/Chitosan/PVA/HPMC E Series Films
*All values are mean ± SD, (n=3)
Sr Formulatio Film Appearance Disintegra Remark
No. ns forming tion Time Sr Film Disintegrat
Formulati
capacit *(sec) No forming Appearance ion Time Remark
ons
y . capacity (sec)*
1 P1 Best Transparent … … 1 C1 Average
++
2 P2 Best Transparent … … 2 C2 Average
++
3 P3 Best Transparent … … 3 C3 Average
++
4 P4 Good Transparent … … 4 C4 Average
++
Disinteg
Sr Formula HP Film Appear Disinte
Film N tions MC formi ance gration
Sr Formul ration
forming Appearance
No. ations
capacity
Time o. grad ng Time
(sec)*
es capac (sec)*
1 V1 Good … … used ity
2 V2 Good … … 1 E1 E3
2 E2 E5
3 V3 Average … …
3 E3 E6
4 37 V4 Average … … 4 E4 E15 9/05/2012

38. Table 8: Preparation of Trial Films using combinations of HPMC E and PVA
Sr.No. Components M1 M2 M3 M4 M5
1 Donepezil HCl (mg) … … … … …
2 HPMC E(mg) … … … … …
3 PVA(mg) … … … … …
4 D.W.(ml) … … … … …
Figure 1: The comparative study of M1 to M5 Figure 2: Dissolution profiles of formulations
formulation containing HPMC E and PVA
38 Formulations 9/05/2012

39. Table 10: Preparation of trial films using combinations of HPMC E and PVA with different
plasticizer
Sr.No. Components R1 R2 R3 R4 R5 R6 R7 R8
1 Donepezil HCl(mg) … … … … … … … …
2 HPMC E…(mg) … … … … … … … …
3 PVA(mg) … … … … … … … …
4 Glycerol (ml) … … … … … … … …
5 PEG 400 (ml) … … … … … … … …
6 PG (ml) … … … … … … … …
7 D.W.(ml) … … … … … … … …
Table 11: Evaluation of Trial Films of HPMC E and PVA with different plasticizer
Sr Formulation Appearance Disintegration Thickness Folding
No. s time (sec)* (mm)* endurance*
1 R1 Transparent … … …
2 R2 Transparent … … …
3 R3 Transparent … … …
4 R4 Difficult to remove … … …
5 R5 Transparent … … …
6 R6 Transparent … … …
7 R7 Transparent … … …
39 9/05/2012
8 R8 Difficult to remove … … …

40. Formulations
Figure 3: Effect of Plasticizer on Folding Endurance
Formulations
40
Figure 4: Effect of Plasticizer on DT 9/05/2012

41. Plasticizers
Figure 6: Films of Different batches
41 9/05/2012

42. 42 9/05/2012

43. Components S1 S2 S3 S4 S5 S6 S7 S8 S9
Donepezil HCl
… … … … … … … … …
(mg)
HPMC (mg) … … … … … … … … …
PVA(mg) … … … … … … … … …
Glycerol (ml) … … … … … … … … …
Sucralose (mg) … … … … … … … … …
D.W.(ml) … … … … … … … … …
** Area of the Final film- 2cm X 2cm
***43
Dose of drug per film- 5 mg 9/05/2012

44. Table 12: Evaluation Parameter of Factorial Batches of Fast Dissolving Oral Films
Formulation Thickness Folding
Weight of the Surface
Appearance Endurance
Code film (mg)* (mm)# pH*
*
S1 … … … … …
S2 … … … … …
S3 … … … … …
S4 … … … … …
S5 … … … … …
S6 … … … … …
S7 … … … … …
S8 … … … … …
S9 … … … … …
44 9/05/2012

45. Table 13 : Evaluation of Factorial Batches of Fast Dissolving Oral Films
Formulation Tensile strength Disintegration Drug content per film (2 x
Code (N/mm 2) Time (sec) 2cm)
(mg)
S1
… … …
S2
… … …
S3
… … …
S4
… … …
S5
… … …
S6
… … …
S7
… … …
S8
… … …
S9
45 … … … 9/05/2012

46. Time (min) Cumulative % drug release*
0.1 N HCl Simulated saliva (pH6.8)
1
… …
2
… …
3
… …
4
… …
5
… …
46 9/05/2012
Figure 5: Dissolution profiles of S4 formulations in 0.1 N HCl and in simulated saliva.

47. Table 14: Dissolution data of factorial batches of fast dissolving oral films
Cumulative % Drug Release
TIME
S4
(Min) S1 S2 S3 S5 S6 S7 S8 S9
1 … … … … … … … … …
2 … … … … … … … … …
3 … … … … … … … … …
4 … … … … … … … … …
5 … … … … … … … … …
7 … … … … … … … … …
10 … … … … … … … … …
15 … … … … … … … … …
47 9/05/2012

48. Figure 6: Dissolution profiles of formulations S1 TO S9
48 9/05/2012

49. 49 9/05/2012

50. 50 9/05/2012

51. % D R at 5 min
= +92.38 -… * X1 – …* X2– …. X1*
X2 –0….. *X12+ 0…..* X22
(R2 = 0.9659)
51 9/05/2012

52. 52 9/05/2012

53. 53 9/05/2012

54.  The FTIR and DSC study revealed that, polymers and excipients used were
compatible with drug.
 The Fast dissolving films were formulated using solvent casting technique.
 Amongst all the formulations, formulation containing HPMC E combine
with PVA as film forming polymer has shown excellent in vitro
disintegration time and in vitro cumulative percent drug release , compared
to other formulations.
 Formulation…………………………………………………………………
…………………….was considered as the best formulation.
 From above discussion, it can be concluded that the successful formation
and optimization of fast dissolving films of Donepezil HCl using HPMC
E and PVA. Hence Donepezil Hydrochloride can be conveniently
administered orally in the form of films
54 9/05/2012

55. 1. Aggarwal J, Singh G, Saini S., Fast dissolving films: A novel approach to oral drug delivery. Int
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Film of levocetirizine dihydrochloride , Int J Pharma Tech ,2011;3 (1) :1740-1749
4. Cilurzo F., Minghetti P., Buratti S., Selmin F., Chiara G.. Gennari , Montanari L., Nicotine Fast
Dissolving Films Made of Maltodextrins: A Feasibility Study, AAPS PharmSciTech,2010.
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9. Reinhart M. , Pivotal Bioequivalence study for Drug Rapidfilm® successfully completed ,
55 Labtec_Press Release_Dummy.rtf dated on 01/14/08 9/05/2012

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56 9/05/2012

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57 9/05/2012

58. 1. Patil S. L*., Mahaparale P. R. , Fast Dissolving Oral Films: An Innovative
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2 Patil S.L*., . Mahaparale P.R., Screening of the polymers for formulation of
oral fast dissolving film, published in Inventi Rapid Pharm Tech, 2012 ;
1 :1,3
3.
………………………………………………………………………………
……communicated to AAPS PharmSciTech.
58 9/05/2012

59. Now…..May be
Donepezil is
available in FD
Films
59
Thank You ... . 9/05/2012